Process for preparing biphenyl imidazole compounds

ABSTRACT

The invention provides processes for preparing intermediates useful for preparing compounds of the formula: 
                         
or a salt thereof, where R 1-3  are as defined in the specification.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No.12,891,964, filed Sep. 28, 2010, now allowed, which claims the benefitof U.S. Provisional Application No. 61/246,608, filed on Sep. 29, 2009;the entire disclosures of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to processes and intermediates forpreparing biphenyl imidazole compounds that are useful in preparingcompounds having angiotensin II type 1 receptor antagonist activity andneprilysin-inhibition activity.

2. State of the Art

Commonly-assigned U.S. Publication Nos. 2008/0269305 and 2009/0023228,both to Allegretti et al. filed on Apr. 23, 2008, disclose novelcompounds that possess AT₁ receptor antagonist activity and neprilysin(NEP) enzyme inhibition activity, the disclosures of which areincorporated herein by reference. In one embodiment, these applicationsdisclose novel compounds such as4′-{2-ethoxy-4-ethyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid.

When preparing compounds for long term storage and when preparingpharmaceutical compositions and formulations, it is often desirable tohave a crystalline form of the therapeutic agent that is neitherhygroscopic nor deliquescent. It is also advantageous to have acrystalline form that has a relatively high melting point, which allowsthe material to be processed without significant decomposition. Acrystalline freebase form of4′-{2-ethoxy-4-ethyl-5-[((S)-2-mercapto-4-methylpentanoylamino)-methyl]imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid is disclosed in commonly-assigned U.S. Publication No.2010/0081697, to Chao et al. filed on Sep. 29, 2009, the disclosure ofwhich is incorporated herein by reference.

The compounds disclosed in these publications and applications areprepared by techniques that typically require that one or more biphenylimidazole intermediates are purified by chromatography. There areseveral advantages to developing processes where such purification stepsare not necessary. This invention addresses that need.

SUMMARY OF THE INVENTION

The present invention relates to novel intermediates and improvedprocesses for preparing intermediates useful for preparing compounds offormula IV:

or a salt thereof, where R¹ is —C₁₋₆alkyl; R² is —O—C₁₋₅alkyl; and R³ is—C₁₋₆alkyl, —C₀₋₃alkylenearyl, —C₀₋₃alkyleneheteroaryl, or—C₀₋₃alkylene-C₃₋₇cycloalkyl. In one particular embodiment, theinvention relates to processes for preparing intermediates useful forpreparing4′-{2-ethoxy-4-ethyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid.

One aspect of the invention relates to a process for preparing acompound of formula I:

where R² is —O—C₁₋₅alkyl; and P is a carboxylic acid protecting group;the process comprising the step of reacting a compound of formula 1:

with a compound of formula 2:

in an organic diluent and a basic aqueous diluent in the presence of aphase transfer catalyst, where the diluents are substantiallyimmiscible, to form a compound of formula I.

In one embodiment, this process further comprises the step of preparinga crystalline form of the compound of formula I. One aspect of theinvention relates to crystalline4′-(4-bromo-2-ethoxy-5-formylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid tert-butyl ester.

Another aspect of the invention relates to a process for preparing acompound of formula II:

or a salt thereof; where R¹ is —C₁₋₆ alkyl; R² is —O—C₁₋₅alkyl; and P isa carboxylic acid protecting group; the process comprising the steps of:

(a) reacting a compound of formula I:

with a potassium-C₁₋₆alkyl-trifluoroborate reagent in the presence of apalladium-phosphine catalyst to form a compound of formula 3:

(b) reacting the compound of formula 3 with hydroxylamine or a saltthereof to form a compound of formula 4:

and

(c) reacting the compound of formula 4 with a reducing agent to form acompound of formula II or a salt thereof.

In one embodiment, this process further comprises the step of preparinga crystalline form of the compound of formula II. One aspect of theinvention relates to crystalline4′-(5-aminomethyl-2-ethoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester.

Yet another aspect of the invention relates to a process for preparing acompound of formula III:

or a salt thereof; where R¹ is —C₁₋₆alkyl; R² is —O—C₁₋₅alkyl; R³ is—C₁₋₆alkyl, —C₀₋₃alkylenearyl, —C₀₋₃alkyleneheteroaryl, or—C₀₋₃alkylene-C₃₋₇cycloalkyl; and R⁴ is —C₁₋₆alkyl,—C₀₋₆alkylene-C₃₋₇cycloalkyl, —C₀₋₆alkylenearyl, or—C₀₋₆alkylenemorpholine; the process comprising the steps of:

(a) reacting a compound of formula I:

with a potassium-C₁₋₆alkyl-trifluoroborate reagent in the presence of apalladium-phosphine catalyst to form a compound of formula 3:

where P is a carboxylic acid protecting group;

(b) reacting the compound of formula 3 with hydroxylamine or a saltthereof to form a compound of formula 4:

(c) reacting the compound of formula 4 with a reducing agent to form acompound of formula II or a salt thereof.

(d) reacting the compound of formula II or a salt thereof with acompound of formula 5:

or a salt thereof, in the presence of an amine-carboxylic acid couplingreagent to form a compound of formula 6:

or a salt thereof; and

(e) removing the carboxylic acid protecting group, P, from the compoundof formula 5 or a salt thereof, to form a compound of formula III or asalt thereof.

In one embodiment, this process further comprises the step of preparinga crystalline form of the compound of formula III. One aspect of theinvention relates to crystalline4′-{5-[(S)-2-acetylsulfanyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid.

Another aspect of the invention relates to a novel intermediates used inthe processes of the invention. In one such aspect of the inventionnovel intermediates have formula 3 or 4.

BRIEF DESCRIPTION OF THE DRAWINGS

Various aspects of the present invention are illustrated by reference tothe accompanying drawings.

FIG. 1 shows a powder x-ray diffraction (PXRD) pattern of thecrystalline form of4′-(5-aminomethyl-2-ethoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (formula IIa).

FIG. 2 shows a differential scanning calorimetry (DSC) thermograph and athermal gravimetric analysis (TGA) for this crystalline compound.

FIG. 3 shows a powder x-ray diffraction (PXRD) pattern of thecrystalline form of4′-{5-[((S)-2-acetylsulfanyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid (formula IIIa).

FIG. 4 shows a DSC thermograph and a TGA for this crystalline compound.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to novel processes for preparing compounds offormula I:

and compounds of formula II:

and compounds of formula III:

or a salt thereof.

The R¹ moiety is —C₁₋₆alkyl, examples of which include —CH₃ and —CH₂CH₃.In one particular embodiment, R¹ is —CH₂CH₃.

The R² moiety is. —O—C₁₋₅alkyl, examples of which include —OCH₃,—OCH₂CH₃, —OCH(CH₃)₂, —O(CH₂)₂CH₃, —O(CH₂)₃CH₃, and —OCH₂CH(CH₃)₂. Inone particular embodiment, R² is —O—CH₂CH₃.

The R³ moiety is selected from —C₁₋₆alkyl, —C₀₋₃alkylenearyl,—C₀₋₃alkyleneheteroaryl, and —C₀₋₃alkylene-C₃₋₇cycloalkyl. Examples of—C₁₋₆alkyl include —CH₃, —CH₂CH₃, —CH(CH₃)₂, —(CH₂)₂CH₃, —(CH₂)₃CH₃,—CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, —(CH₂)₂CH(CH₃)₂, and—(CH₂)₄CH₃. In one particular embodiment, R³ is —CH₂CH(CH₃)₂. Examplesof —C₀₋₃alkylenearyl include phenyl, benzyl, —CH₂-biphenyl,—(CH₂)₂-phenyl and —CH₂-naphthalen-1-yl. Examples of—C₀₋₃alkyleneheteroaryl include —CH₂-pyridyl, —CH₂-furanyl,—CH₂-thienyl, and —CH₂-thiophenyl. Examples of—O₀₋₃alkylene-C₃₋₇cycloalkyl include —CH₂-cyclopropyl, cyclopentyl,—CH₂-cyclopentyl, -cyclohexyl, and —CH₂-cyclohexyl.

The R⁴ moiety is selected from —C₁₋₆alkyl, —C₀₋₆alkylene-C₃₋₇cycloalkyl,—C₀₋₆alkylenearyl, and —C₀₋₆alkylenemorpholine. Examples of —C₁₋₆ alkylinclude —CH₃, —CH₂CH₃, —CH(CH₃)₂, —C(CH₃)₃, and —CH₂CH(CH₃)₂. In oneparticular embodiment, R⁴ is —CH₃. Examples of—C₀₋₆alkylene-C₃₋₇cycloalkyl include -cyclopentyl, -cyclohexyl, and—CH₂-cyclopentyl. Examples of —C₀₋₆alkylenearyl include phenyl. Examplesof —C₀₋₆alkylenemorpholine include —CH₂-morpholine and—(CH₂)₂-morpholine.

The P moiety is a “carboxylic acid protecting group”, a term used hereinto mean a group covalently attached to a carboxyl functional group thatprevents the functional group from undergoing undesired reactions butwhich permits the functional group to be regenerated (i.e., deprotectedor unblocked) upon treatment of the protecting group with a suitablereagent. Representative carboxylic acid protecting groups include, butare not limited to, methyl, ethyl, t-butyl, benzyl (Bn), p-methoxybenzyl(PMB), 9-fluorenylmethyl (Fm), trimethylsilyl (TMS),t-butyldimethylsilyl (TBDMS), diphenylmethyl (benzhydryl, DPM), and thelike. In one particular embodiment, P is t-butyl. Other representativecarboxylic acid protecting group are described, for example, in T. W.Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, ThirdEdition, Wiley, New York, 1999.

Definitions

When describing the compounds and processes of the invention, thefollowing terms have the following meanings unless otherwise indicated.Additionally, as used herein, the singular forms “a,” “an” and “the”include the corresponding plural forms unless the context of use clearlydictates otherwise. The terms “comprising”, “including,” and “having”are intended to be inclusive and mean that there may be additionalelements other than the listed elements. All numbers expressingquantities of ingredients, properties such as molecular weight, reactionconditions, and so forth used herein are to be understood as beingmodified in all instances by the term “about,” unless otherwiseindicated. Accordingly, the numbers set forth herein are approximationsthat may vary depending upon the desired properties sought to beobtained by the present invention. At least, and not as an attempt tolimit the application of the doctrine of equivalents to the scope of theclaims, each number should at least be construed in light of thereported significant digits and by applying ordinary roundingtechniques.

The compounds described herein have typically been named using theAutoNom feature of the commercially-available MDL® ISIS/Draw software(Symyx, Santa Clara, Calif.).

As used herein, the phrase “having the formula” or “having thestructure” is not intended to be limiting and is used in the same waythat the term “comprising” is commonly used.

The term “alkyl” means a monovalent saturated hydrocarbon group whichmay be linear or branched. Unless otherwise defined, such alkyl groupstypically contain from 1 to 10 carbon atoms and include, for example,—C₁₋₅alkyl and —C₁₋₆alkyl. Representative alkyl groups include, by wayof example, methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl,isobutyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl,n-decyl, and the like.

When a specific number of carbon atoms is intended for a particular termused herein, the number of carbon atoms is shown preceding the term assubscript. For example, the term “—C₁₋₆alkyl” means an alkyl grouphaving from 1 to 6 carbon atoms, and the term “C₃₋₇cycloalkyl” means acycloalkyl group having from 3 to 7 carbon atoms, where the carbon atomsare in any acceptable configuration.

The term “alkylene” means a divalent saturated hydrocarbon group thatmay be linear or branched. Unless otherwise defined, such alkylenegroups typically contain from 0 to 10 carbon atoms and include, forexample, —C₀₋₃alkylene- and —C₀₋₆alkylene-. Representative alkylenegroups include, by way of example, methylene, ethane-1,2-diyl(“ethylene”), propane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl, and the like. It is understood that when the alkyleneterm include zero carbons such as —C₀₋₃alkylene-, such terms areintended to include a single bond.

The term “aryl” means a monovalent aromatic hydrocarbon having a singlering (for example, phenyl) or fused rings. Fused ring systems includethose that are fully unsaturated (for example, naphthalene) as well asthose that are partially unsaturated (for example,1,2,3,4-tetrahydronaphthalene). Unless otherwise defined, such arylgroups typically contain from 6 to 10 carbon ring atoms and include, forexample, —C₆₋₁₀aryl. Representative aryl groups include, by way ofexample, phenyl and naphthalene-1-yl, naphthalene-2-yl, and the like.

The term “cycloalkyl” means a monovalent saturated carbocyclichydrocarbon group. Unless otherwise defined, such cycloalkyl groupstypically contain from 3 to 10 carbon atoms and include, for example,—C₃₋₆cycloalkyl and —C₃₋₇cycloalkyl. Representative cycloalkyl groupsinclude, by way of example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and the like.

The term “heteroaryl” means a monovalent aromatic group having a singlering or two fused rings and containing in the ring(s) at least oneheteroatom (typically 1 to 3) selected from nitrogen, oxygen and sulfur.Unless otherwise defined, such heteroaryl groups typically contain from5 to 10 total ring atoms and include, for example, —C₂₋₉heteroaryl.Representative heteroaryl groups include, by way of example, monovalentspecies of pyrrole, imidazole, thiazole, oxazole, furan, thiophene,triazole, pyrazole, isoxazole, isothiazole, pyridine, pyrazine,pyridazine, pyrimidine, triazine, indole, benzofuran, benzothiophene,benzoimidazole, benzthiazole, quinoline, isoquinoline, quinazoline,quinoxaline, and the like, where the point of attachment is at anyavailable carbon or nitrogen ring atom.

The term “melting point” as used herein means the temperature at whichthe maximum endothermic heat flow is observed by differential scanningcalorimetry, for the thermal transition that corresponds to thesolid-to-liquid phase change.

The term “salt” when used in conjunction with a compound means a salt ofthe compound derived from an inorganic or organic base or from aninorganic or organic acid. Salts derived from inorganic bases includealuminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, manganous, potassium, sodium, zinc, and the like.Particularly preferred are ammonium, calcium, magnesium, potassium andsodium salts. Salts derived from organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occurring amines, and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperadine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like. Salts derived from acidsinclude acetic, ascorbic, benzenesulfonic, benzoic, camphosulfonic,citric, ethanesulfonic, fumaric, gluconic, glucoronic, glutamic,hippuric, hydrobromic, hydrochloric, isethionic, lactic, lactobionic,maleic, malic, mandelic, methanesulfonic, mucic, naphthalenesulfonic,nicotinic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric,tartaric, p-toluenesulfonic, and the like. Particularly preferred arecitric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric andtartaric acids. In addition, when a compound of contains both a basicmoiety, such as an amine or imidazole, and an acidic moiety such as acarboxylic acid, zwitterions may be formed and are included within theterm “salt” as used herein. The term “pharmaceutically acceptable salt”means a salt prepared from a base or an acid which is acceptable foradministration to a patient, such as a mammal (e.g., salts havingacceptable mammalian safety for a given dosage regime). However, it isunderstood that the salts covered by the invention are not required tobe pharmaceutically acceptable salts, such as salts of intermediatecompounds that are not intended for administration to a patient.

Process Conditions

Suitable inert diluents for use in the process of the invention include,by way of illustration and not limitation, organic diluents such asacetic acid, tetrahydrofuran (THF), acetonitrile (MeCN),N,N-dimethylformamide (DMF), N,N-dimethylacetamide,N-methylpyrrolidinone, dimethyl sulfoxide (DMSO), toluene,dichloromethane (DCM), acetone, ethyl acetate, isopropyl acetate, methylt-butyl ether, chloroform (CHCl₃), carbon tetrachloride (CCl₄),1,4-dioxane, methanol, ethanol, propanol, isopropanol, butanol, ethyleneglycol, and the like. Aqueous diluents may also be used, and includewater as well as basic and acidic aqueous diluents. Combinations of anyof the foregoing diluents are also contemplated.

Suitable polar, protic solvents for use in the process of the inventioninclude, by way of illustration and not limitation, methanol, ethanol,propanol, isopropanol, butanol, ethylene glycol, water, acetic acid, andthe like.

There are numerous bases that are suitable for use in the process of theinvention. Exemplary organic bases include, by way of illustration andnot limitation: amines including primary alkylamines (e.g., methylamine,ethanolamine, the buffering agent tris, and the like), secondaryalkylamines (e.g., dimethylamine, methylethanolamine,N,N-diisopropylethylamine (DIPEA), and the like), tertiary amines (e.g.,trimethylamine, triethylamine, and the like); ammonia compounds such asammonium hydroxide and hydrazine; alkali metal hydroxides such as sodiumhydroxide, sodium methoxide, potassium hydroxide, potassium t-butoxide,and the like; metal hydrides; and alkali metal carboxylate salts such assodium acetate and the like). Exemplary inorganic bases, include, by wayof illustration and not limitation: alkali metal carbonates such aslithium carbonate, potassium carbonate, cesium carbonate, sodiumcarbonate, sodium bicarbonate, and the like; other carbonates such ascalcium carbonate and the like; and alkali metal phosphates such aspotassium phosphate and the like).

There are numerous acids that are suitable for use in the process of theinvention, and include, by way of illustration and not limitation,boric, carbonic, nitric (HNO₃), phosphoric (H₃PO₄), sulfamic andsulfuric (H₂SO₄) acids, as well as hydrohalic acids such as hydrobromic(HBr), hydrochloric (HCl), hydrofluoric (HF), and hydroiodic (HI) acid.

Upon completion of any of the process steps, the resulting mixture orreaction product may be further treated in order to obtain the desiredproduct. For example, the resulting mixture or reaction product may besubjected to one or more of the following procedures: concentrating orpartitioning (for example, between EtOAc and water or between 5% THF inEtOAc and 1M phosphoric acid); extraction (for example, with EtOAc,CHCl₃, DCM, HCl); washing (for example, with ethanol, heptanes,saturated aqueous NaCl, saturated NaHCO₃, Na₂CO₃ (5%), CHCl₃ or 1MNaOH); distillation; drying (for example, over MgSO₄, over Na₂SO₄, undernitrogen, or under reduced pressure); precipitation; filtration;crystallizing (for example, from ethanol, heptanes or isopropylacetate); and/or being concentrated (for example, in vacuo).

Upon completion of any of the crystallization steps, the crystallinecompound can be isolated from the reaction mixture by any conventionalmeans such as precipitation, concentration, centrifugation, drying (forexample, at room temperature), and the like.

The process for preparing a compound of formula I is a one stepalkylation reaction, which involves combining an imidazole compound offormula 1 with a biphenyl compound of formula 2 to form a compound offormula I. Compounds of formula 1 and 2 can be prepared by conventionalprocedures using commercially available starting materials andconventional reagents. For example, see the Preparations describedherein as well as U.S. Publication Nos. 2008/0269305 and 2009/0023228,both to Allegretti et al.

In one embodiment, a slight excess of the imidazole compound of formula1 is used based on the amount of the biphenyl compound of formula 2. Inone embodiment, from about 1 to about 2 equivalents of the imidazole areused, and in another embodiment, about 1 to 1.5 equivalents are used.

Typically, the compounds of formula 1 and 2 are combined in an organicdiluent and a basic aqueous diluent in the presence of a phase transfercatalyst. In one embodiment, a slight excess of the basic aqueousdiluent is used based on the amount of the imidazole compound offormula 1. In one embodiment, from about 1 to about 2 equivalents of thebasic aqueous diluent are used, and in another embodiment, about 1 to1.5 equivalents are used.

Exemplary phase transfer catalysts include quaternary ammonium saltssuch as tetrabutylammonium bromide (Bu₄NBr), didecyldimethylammoniumbromide (DDAB), methyltriphenylphosphonium bromide,methyltridecylammonium chloride, and the like; and in one embodiment istetrabutylammonium bromide. In one embodiment, from about 0.01 to about1.0 equivalents of a phase transfer catalyst are used based on theamount of the biphenyl compound of formula 2; and in another embodiment,about 0.03 to about 0.07 equivalents are used.

The organic diluent and the basic aqueous diluent are substantiallyimmiscible, which means that the two diluents do not mix to form asolution, i.e., they are substantially insoluble in each other andusually exist in separate phases when mixed; noting, however, that therecould potentially be a small amount of mixing between the two diluentsat their interface. In one embodiment the organic diluent is toluene andthe basic aqueous diluent is NaOH.

Formation of the compound of formula I is typically conducted at atemperature ranging from about 20° C. to about 40° C.; and in oneembodiment at a temperature ranging from about 25° C. to about 35° C.for about 24 to about 72 hours, and in one embodiment for about 48 to 60hours, or until formation of the compound of formula I is substantiallycomplete.

When formation of the compound of formula I is substantially complete,the resulting product is then isolated and purified by conventionalprocedures. The compound of formula I is optionally crystallized bytreatment with ethanol to complete dissolution, cooling to effectcrystallization, and isolating the resulting solids to yield thecrystalline material. Typically dissolution is conducted at atemperature ranging from about 40° C. to about 70° C., and in oneembodiment at a temperature ranging from about 50° C. to 60° C. Thecooling step is done at a temperature ranging from about 0° C. to about10° C., and in one embodiment at a temperature ranging from about 2° C.to 6° C., for about 2 to 6 hours, or until formation of crystals. Uponcompletion of the crystallization step, the crystalline compound offormula I can be isolated from the reaction mixture by any conventionalmeans.

Previous methods of preparing compounds of formula I often resulted inobtaining a high percentage of formula 1 by-products, often as high as15%. Use of an organic diluent and a basic aqueous diluent, incombination with a phase transfer catalyst, as in the present method,has reduced the amount of by-product to less than 2%, providing areaction with better selectivity than in prior methods.

The process for preparing a compound of formula II or a salt thereof isconducted in three steps. The first step of the process is a Suzukicoupling reaction, which involves combining one equivalent of analdehyde of formula I with one or more equivalents of apotassium-C₁₋₆alkyl-trifluoroborate reagent in the presence of apalladium-phosphine catalyst to form a compound of formula 3.

Aldehydes of formula I used in the process of the invention can be madeby the methods described herein or can be prepared by conventionalprocedures using commercially available starting materials andconventional reagents. For example, see the Preparations describedherein as well as U.S. Publication Nos. 2008/0269305 and 2009/0023228,both to Allegretti et al., which describes various methods for preparingsuch compounds.

Typically, the aldehyde of formula I and thepotassium-C₁₋₆alkyl-trifluoroborate reagent are combined with thepalladium-phosphine catalyst in an inert diluent in the presence of anexcess amount of a suitable base to form a reaction mixture. In oneembodiment, from about 1 to about 2 equivalents of thepotassium-C₁₋₆alkyl-trifluoroborate reagent are used based on the amountof aldehyde; and in another embodiment, about 1.4 to about 1.5equivalents are used.

The potassium-C₁₋₆alkyl-trifluoroborate reagent is selected based uponthe desired R¹ group. For example, to prepare a compound of formula 3where R¹ is ethyl, a suitable potassium-C₁₋₆alkyl-trifluoroboratereagent is potassium ethyl trifluoroborate.

The palladium-phosphine catalyst may be a single catalyst containingpalladium and phosphine, such as bis(triphenylphosphine)palladium(II),tetrakis(triphenylphosphine)-palladium(0) (Pd(PPh₃)₄),[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II),bis[1,2-bis(diphenylphosphino)propane]palladium(0), and the like.Alternately, the palladium-phosphine catalyst may be a combination of apalladium catalyst and a source of phosphine. Exemplary palladiumcatalysts include palladium(II)acetate (Pd(OAc)₂), palladium(II)chloride(PdCl₂), and the like. Suitable sources of phosphine includedi(1-adamantyl)-n-butylphosphine, triphenylphosphine,ethyldiphenylphosphine, dicyclohexyl-phenylphosphine,2-pyridyldiphenylphosphine, bis(6-methyl-2pyridyl)phenylphosphine,tri-p-chlorophenylphosphine, tri-pmethoxyphenylphosphine, and the like.In one embodiment, the palladium catalyst is palladium(II)acetate andthe source of phosphine is di(1-adamantyl)-n-butylphosphine.

In one embodiment, from about 0.01 to about 0.04 equivalents of apalladium catalyst and about 0.02 to about 0.06 equivalents of aphosphine source are used based on the amount of aldehyde; and inanother embodiment, about 0.02 to about 0.03 equivalents of a palladiumcatalyst and about 0.03 to about 0.05 equivalents of a phosphine sourceare used. In another embodiment, from about 0.03 to about 0.1equivalents of a palladium-phosphine catalyst is used based on theamount of aldehyde; and in another embodiment, about 0.05 to about 0.08equivalents are used.

An excess amount of base is used, typically from about 3.0 to about 6.0equivalents based on the amount of aldehyde, and in one embodiment,about 3.0 to about 4.0 equivalents. In one embodiment, the inert diluentis a mixture of toluene and water. In another embodiment the base is analkali metal carbonate such as cesium carbonate.

Formation of the compound of formula 3 is typically conducted at atemperature ranging from about 80° C. to about 100° C.; and in oneembodiment at a temperature ranging from about 85° C. to about 95° C.for about 12 to about 20 hours, and in one embodiment for about 14 to 18hours, or until formation of the compound of formula 3 is substantiallycomplete. When formation of the compound of formula 3 is substantiallycomplete, the resulting product is then isolated and purified byconventional procedures. In one embodiment the compound of formula 3 isobtained in solution.

The second step of the process is an oxime-forming step, which involvescombining one equivalent of the aldehyde of formula 3 with one or moreequivalents of hydroxylamine or a salt thereof to form an oxime offormula 4.

Typically, the compound of formula 3 and the hydroxylamine or a saltthereof are combined in the presence of an excess amount of a suitablebase to form a reaction mixture. In one embodiment, from about 1 toabout 2 equivalents of the hydroxylamine or a salt thereof are usedbased on the amount of compound of formula 3; and in another embodiment,about 1.4 to about 1.5 equivalents are used.

An excess amount of base is used, typically from about 3.0 to about 6.0equivalents based on the amount of compound of formula 3, and in oneembodiment, about 3.0 to about 4.0 equivalents. In one embodiment thebase is an alkali metal carbonate such as sodium bicarbonate.

Formation of the oxime of formula 4 is typically conducted at atemperature ranging from about 20° C. to about 60° C.; and in oneembodiment at a temperature ranging from about 30° C. to about 50° C.for about 20 to about 28 hours, and in one embodiment for about 22 to 26hours, or until formation of the oxime is substantially complete. Whenformation of the oxime is substantially complete, the resulting productis then isolated and purified by conventional procedures.

The third step of the process is the reduction of the oxime to a primaryamine, and involves reacting the oxime of formula 4 with a reducingagent to form an amine of formula II or a salt thereof.

Exemplary reducing agents are those suited for reducing the oxime to anamine, and include hydrogen/Raney nickel, palladium on carbon (Pd/C),and Zn—HCl. Typically, the oxime of formula 4 and the reducing agent arecombined in a polar, protic solvent and an amine base to form a reactionmixture. Formation of the amine is typically conducted at ambienttemperature for about 1 to about 5 hours, and in one embodiment forabout 2 to 4 hours, or until formation of the amine is substantiallycomplete. In one embodiment, the amine base is ammonium hydroxide andthe solvent is ethanol.

When formation of the amine is substantially complete, the resultingproduct is then isolated and purified by conventional procedures. Theamine is optionally crystallized by treatment with heptanes to completedissolution, cooling to effect crystallization, and isolating theresulting solids to yield the crystalline material. Typically thecooling step is done at a temperature ranging from about 0° C. to about10° C., and in one embodiment at a temperature ranging from about 2° C.to 6° C., for about 22 to 26 hours, or until formation of crystals. Uponcompletion of the crystallization step, the crystalline compound offormula II or a salt thereof can be isolated from the reaction mixtureby any conventional means.

The process for preparing a compound of formula III or a salt thereof isconducted in five steps. The first, second and third steps are describedabove with reference to the process of preparing compound of formula II.

The fourth step of the process is a coupling step, which involvesreacting one equivalent of the amine of formula II or a salt thereofwith one or more equivalents of a carboxylic acid of formula 5 or a saltthereof, in the presence of one or more equivalents of anamine-carboxylic acid coupling reagent to form a compound of formula 6or a salt thereof.

Carboxylic acids of formula 5 used in the process of the invention areknown in the art and are either commercially available or can beprepared by conventional procedures using commercially availablestarting materials and conventional reagents. For example, see thePreparations described herein as well as U.S. Publication Nos.2008/0269305 and 2009/0023228, both to Allegretti et al., whichdescribes various methods for preparing such compounds.

Typically, the amine or a salt thereof and the carboxylic acid or a saltthereof are combined in an inert diluent in the presence of a couplingreagent to form a reaction mixture. In one embodiment, from about 1 toabout 2 equivalents of the carboxylic acid are used based on the amountof amine; and in another embodiment, about 1.1 to about 1.3 equivalentsare used. In one embodiment, from about 1 to about 2 equivalents of thecoupling reagent are used based on the amount of amine; and in anotherembodiment, about 1.1 to about 1.3 equivalents are used. Exemplary inertdiluents include dichloromethane and isopropyl acetate.

Suitable amine-carboxylic acid coupling reagents include(2-(6-chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminiumhexafluorophosphate) (HCTU),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate(PyBOP), O-(7-azabenzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), dicyclohexylcarbodiimide (DCC),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC),carbonyldiimidazole (CDI), and the like; and in one particularembodiment, the coupling reagent is HCTU.

The coupling reaction is typically conducted at a temperature rangingfrom about −5° C. to about 5° C.; and in one embodiment at a temperatureranging from about −1° C. to about 3° C. for about 5 to about 15 hours,or until formation of the compound of formula 6 is substantiallycomplete. The pH of the reaction mixture is adjusted to about 5 to about5 by addition of a suitable acid, such as 1N hydrochloric acid. Whenformation of the compound of formula 6 is substantially complete, theresulting product is then isolated and purified by conventionalprocedures.

The fifth step of the process is a deprotection step, which involvesremoving the carboxylic acid protecting group, P, from the compound offormula 6 or a salt thereof, to form a compound of formula III or a saltthereof.

Standard deprotection techniques and reagents are used to remove the Pgroup, and may vary depending upon which group is used. For example,NaOH is commonly used when P is methyl, an acid such as TFA or HCl iscommonly used when P is t-butyl, and catalytic hydrogenation conditionsuch as H₂ (1 atm) and 10% Pd/C in alcoholic solvent (“H₂/Pd/C”) may beused when P is benzyl. In one particular embodiment, TFA is used.

Typically, the compound of formula 6 or a salt thereof and thedeprotecting reagent are combined in an inert diluent. An excess amountof reagent is used; in one embodiment from about 10 to about 30equivalents of the reagent are used based on the amount of the compoundof formula 6. In one embodiment, the inert diluent is anhydrous, such astetrahydrofuran, dichloromethane, N,N-dimethylformamide, and1,4-dioxane.

This deprotection step is typically conducted at a temperature rangingfrom about 10° C. to about 30° C.; and in one embodiment at atemperature ranging from about 15° C. to about 25° C. for about 12 toabout 20 hours, and in one embodiment for about 14 to 18 hours, or thereaction is substantially complete. The pH of the reaction mixture isthen adjusted to about 6 to about 7 by addition of a suitable base, suchas aqueous potassium carbonate.

When formation of the compound of formula III is substantially complete,the resulting product is then isolated and purified by conventionalprocedures. The compound of formula III is optionally crystallized bytreatment with isopropyl acetate to complete dissolution, cooling toeffect crystallization, and isolating the resulting solids to yield thecrystalline material. Typically the cooling step is done at atemperature ranging from about 0° C. to about 10° C., and in oneembodiment at a temperature ranging from about 2° C. to 6° C., for about14 to 18 hours, or until formation of crystals. Upon completion of thecrystallization step, the crystalline compound of formula III can beisolated from the reaction mixture by any conventional means.

The compound of formula III can then be used to prepare compound offormula IV, by converting the thioester group, —SC(O)—R⁴ to a thiol,—SH. This can be done by conventional methods such as by treatment withbases such as sodium hydroxide, sodium methoxide, primary alkylamines,and hydrazine.

Crystalline Properties

One exemplary compound of formula I is4′-(4-bromo-2-ethoxy-5-formylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid tert-butyl ester, which is represented by formula Ia:

In one embodiment, the compound of formula Ia is in a crystalline form.

One exemplary compound of formula II is4′-(5-aminomethyl-2-ethoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester, which is represented by formula IIa:

In one embodiment, the compound of formula IIa is in a crystalline form.In another embodiment, the crystalline form is not associated with anycounterions and is referred to as a freebase crystalline form.

One exemplary compound of formula III is4′-{5-[((S)-2-acetylsulfanyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid, which is represented by formula IIIa:

In one embodiment, the compound of formula IIIa is in a crystallineform. In another embodiment, the crystalline form is a zwitterion.

As is well known in the field of powder x-ray diffraction, relative peakheights of PXRD spectra are dependent on a number of factors relating tosample preparation and instrument geometry, while peak positions arerelatively insensitive to experimental details. A PXRD pattern wasobtained as set forth in Example 4. Thus, in one embodiment, thecrystalline compounds of the invention are characterized by a PXRDpattern having certain peak positions.

The crystalline form of4′-(5-aminomethyl-2-ethoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (formula IIa) is characterized by a PXRD pattern inwhich the peak positions are substantially in accordance with thoseshown in FIG. 1. Those peaks are listed below, in order of descendingrelative intensity.

I % 2-Theta 100 31.91 87 20.63 72 10.43 57 15.65 53 23.96 32 18.20 2524.86 24 12.74 24 23.03 18 5.24 16 14.90 14 21.71Thus, in one embodiment, the crystalline form of formula IIa ischaracterized by a powder x-ray diffraction (PXRD) pattern comprisingdiffraction peaks at 2θ values of 5.24±0.2, 10.43±0.2, 15.65±0.2,20.63±0.2, and 31.91±0.2; and further characterized by comprising one ormore additional diffraction peaks at 2θ values selected from 12.74±0.2,14.90±0.2, 18.20±0.2, 21.71±0.2, 23.03±0.2, 23.96±0.2, and 24.86±0.2.

The crystalline form of4′-{5-[((S)-2-acetylsulfanyl-4-methylpentanoylamino)-methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid (formula IIIa) is characterized by a PXRD pattern in which the peakpositions are substantially in accordance with those shown in FIG. 3.Those peaks are listed below, in order of descending relative intensity.

I % 2-Theta 100 7.16 61 23.24 57 20.12 53 13.68 48 15.98 41 8.10 3620.78 30 26.28 26 12.06 24 16.62 21 5.24 13 11.26Thus, in one embodiment, the crystalline form of formula IIIa ischaracterized by a powder x-ray diffraction (PXRD) pattern comprisingdiffraction peaks at 2θ values of 5.24±0.2, 7.16±0.2, 13.68±0.2, and15.98±0.2; and further characterized by comprising one or moreadditional diffraction peaks at 2θ values selected from 8.10±0.2,11.26±0.2, 12.06±0.2, 16.62±0.2, 20.12±0.2, 20.78±0.2, 23.24±0.2, and26.28±0.2.

Differential scanning calorimetry (DSC) traces were obtained as setforth in Example 5. Thus, in one embodiment, the crystalline compoundsof the invention are characterized by their DSC thermographs. In oneembodiment, the crystalline form of formula IIa is characterized by aDSC thermograph which shows a melting point of about 76.0° C., with nosignificant thermal decomposition below about 150.0° C., as seen in FIG.2. In one embodiment, the crystalline form of formula IIIa ischaracterized by a DSC thermograph which shows a melting point of about130.9° C., with no significant thermal decomposition below about 150.0°C., as seen in FIG. 4.

Thermogravimetric analysis (TGA) was performed on the crystallinecompounds of the invention as described in Example 5. Thus, in oneembodiment, the crystalline compounds of the invention are characterizedby their TGA trace. In one embodiment, the crystalline form of formulaIIa is characterized by a TGA trace which shows a loss of solventsand/or water (<0.5%) at temperatures below about 150° C. (which issignificantly higher than the melting point), as seen in FIG. 2. In oneembodiment, the crystalline form of formula Ma is characterized by a TGAtrace which shows a loss of solvents and/or water (<0.5%) attemperatures below about 150° C. (which is significantly higher than themelting point), as seen in FIG. 4.

These properties of the crystalline compounds of the invention arefurther illustrated in the Examples below.

EXAMPLES

The following Preparations and Examples are provided to illustratespecific embodiments of this invention. These specific embodiments,however, are not intended to limit the scope of this invention in anyway unless specifically indicated.

The following abbreviations have the following meanings unless otherwiseindicated and any other abbreviations used herein and not defined havetheir standard generally accepted meaning:

AcOH acetic acid Bu₄NBr tetrabutylammonium bromide DCC1,3-dicyclohexylcarbodiimide DCM dichloromethane or methylene chlorideDIPEA N,N-diisopropylethylamine DMAP 4-dimethylaminopyridine DMFN,N-dimethylformamide DMSO dimethyl sulfoxide DTT 1,4-dithiothreitolEtOAc ethyl acetate EtOH ethanol HCTU(2-(6-chloro-1H-benzotriazole-1-yl)-1,1,3,3- tetramethylaminiumhexafluorophosphate) IPAc isopropyl acetate MeCN acetonitrile MeOHmethanol MTBE methyl t-butyl ether NaOMe sodium methoxide NBSN-bromosuccinimide TFA trifluoroacetic acid THF tetrahydrofuran

Unless noted otherwise, all materials, such as reagents, startingmaterials and solvents, were purchased from commercial suppliers (suchas Sigma-Aldrich, Fluka Riedel-de Haën, Strem Chemicals, Inc., and thelike) and were used without further purification.

Reactions were run under nitrogen atmosphere, unless noted otherwise.The progress of reactions were monitored by thin layer chromatography(TLC), analytical high performance liquid chromatography (anal. HPLC),and mass spectrometry, the details of which are given in specificexamples. Solvents used in analytical HPLC were as follows: solvent Awas 98% water/2% MeCN/1.0 mL/L TFA; solvent B was 90% MeCN/10% water/1.0mL/L TFA.

Reactions were worked up as described specifically in each preparationor example; commonly reaction mixtures were purified by extraction andother purification methods such as temperature-, and solvent-dependentcrystallization, and precipitation. In addition, reaction mixtures wereroutinely purified by preparative HPLC, typically using Microsorb C18and Microsorb BDS column packings and conventional eluents.Characterization of reaction products was routinely carried out by massand ¹H-NMR spectrometry. For NMR measurement, samples were dissolved indeuterated solvent (CD₃OD, CDCl₃, or DMSO-d₆), and ¹H-NMR spectra wereacquired with a Varian Gemini 2000 instrument (400 MHz) under standardobservation conditions. Mass spectrometric identification of compoundswas typically conducted using an electrospray ionization method (ESMS)with an Applied Biosystems (Foster City, Calif.) model API 150 EXinstrument or an Agilent (Palo Alto, Calif.) model 1200 LC/MSDinstrument.

Preparation 1 5-Bromo-2-ethoxy-3H-imidazole-4-carbaldehyde

2,4,5-Tribromo-1H-imidazole (1a) (98.7 g, 324 mmol, 1.0 cq) wasdissolved into 1.20 L of DCM and cooled to 0° C. To this was added DIPEA(62 mL, 360 mmol, 1.1 eq) followed by the slow addition of[β-(trimethylsilyl)ethoxy]methyl chloride (60.2 mL, 340 mmol, 1.05 eq).The solution was slowly warmed to room temperature. After 2 hours themixture was washed with 1M H₃PO₄/saturated aqueous NaCl (1:10; 2×600mL). The organic layer was dried over MgSO₄, and evaporated to dryness,yielding intermediate (1b) as faint yellow liquid that solidified onstanding (137 g).

Intermediate (1b) (130 g, 290 mmol, 1.0 eq) was dissolved into anhydrousEtOH (650 mL). To this was slowly added potassium t-butoxide (98.6 g,879 mmol, 3.0 eq) and the mixture was heated to reflux for 16 hours. Themixture was then cooled to room temperature, filtered and concentrated.The resulting oil was dissolved in EtOAc (800 mL) and washed withsaturated NaHCO₃ (400 mL). The layers were separated and the organic waswashed with saturated aqueous NaCl, dried over MgSO₄, filtered andconcentrated, yielding intermediate (1c) as a brown oil (115.3 g). MSm/z: [M+H⁺] calcd for C₁₁H₂₀Br₂N₂O₂Si, 401.9 found 401.2.

Intermediate (1c) (69.5 g, 174 mmol, 1.0 eq) was dissolved in anhydrousTHF (600 mL) and cooled to −78° C. under nitrogen. A 2.5M solution ofn-butyllithium in hexanes (72.9 mL, 180 mmol, 1.05 eq) was addeddropwise and the mixture was stirred at −78° C. for 10 minutes. DMF (40mL, 520 mmol, 3.0 eq) was then added and the mixture was stirred at −78°C. for 15 minutes and was then warmed to room temperature. The reactionwas quenched with water (10 mL), diluted with EtOAc (600 mL) and waswashed with water (100 mL), saturated aqueous NaCl, dried over MgSO₄ andconcentrated under reduced pressure. The recovered material was purifiedby silica gel chromatography (15-30% EtOAc:hexanes) to produceintermediate (1d) as a pale yellow oil (45 g). Intermediate (1d) (105.8g, 303 mmol, 1.0 eq) was cooled at 0° C. in ice. TFA (300 mL) was addedand the mixture was stirred at 0° C. for 15 minutes, then warmed to roomtemperature. After 90 minutes the mixture was concentrated under reducedpressure and redissolved in EtOAc (700 mL). The organic was washed withsaturated bicarbonate (2×600 mL), saturated aqueous NaCl, dried overMgSO₄, and concentrated under reduced pressure to produce a yellowsolid. The material was suspended in hexanes (300 mL) and stirred at 0°C. for 30 minutes. The material was filtered and the solid was washedwith cold hexanes (150 mL) to yield the title compound (1) as a palewhite solid (61.2 g). ¹H-NMR (CDCl₃) δ (ppm): 1.4 (m, 3H), 4.5 (m, 2H),5.2 (s, 1H), 9.2 (d, 1H).

Preparation 2 4′-Bromomethyl-3′-fluorobiphenyl-2-carboxylic Acid t-ButylEster

To a solution of 1.0M DCC in DCM (800 mL, 800 mol) cooled at 0° C. wasadded 2-bromobenzoic acid (2a) (161 g, 800 mmol) followed by DMAP (9.0g, 740 mmol) and t-butyl alcohol (82.4 mL, 880 mmol). The mixture wasstirred at room temperature for 10 minutes, then warmed to roomtemperature and stirred. After 16 hours, the mixture was then filtered.The organic was washed with saturated NaHCO₃ (400 mL), saturated aqueousNaCl, dried over MgSO₄, filtered and concentrated under reduced pressureto produce the crude intermediate (2b) as an oil (228.8 g).

The crude intermediate (2b) (109.6 g, 426 mmol) and3-fluoro-4-methylphenyl-boronicacid (72.2 g, 449 mmol) were suspended inisopropyl alcohol (360 mL, 4.7 mmol). A 2.0M solution of sodiumcarbonate in water (360 mL, 720 mmol) was added and the mixture wasdegassed under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (4.9g, 4.3 mmol) was then added and the mixture was stirred at 90° C. for 46hours. The mixture was cooled to room temperature, diluted with EtOAc(800 mL), and the layers were separated. The organic was washed withsaturated aqueous NaCl and concentrated under reduced pressure. Therecovered oil was purified by silica gel chromatography (3×4-6%EtOAc:hexanes) to yield intermediate (2c) as a clear oil (93.3 g).

Intermediate (2c) (89.8 g, 314 mmol, 1.0 eq) was dissolved in CCl₄ (620mL, 6.4 mol) and was degassed under nitrogen. NBS (55.8 g, 314 mmol) wasadded, followed by benzoyl peroxide (1.5 g, 6.3 mmol) and the mixturewas heated at 90° C. under nitrogen for 7 hours. The reaction was cooledin an ice bath, filtered, and concentrated under reduced pressure. Therecovered oil was triturated with 150 mL of 3% EtOAc: hexanes. Thesolution was chilled at −20° C. for 2 hours, then filtered and washedwith cold 3% EtOAc:hexanes solution (200 mL) to yield the title compound(2) as an off white solid (88.9 g). ¹H-NMR (CDCl₃) δ (ppm): 1.3 (m, 9H),4.6 (s, 2H), 7.0-7.1 (m, 2H), 7.3 (dd, 1H), 7.4 (m, 1H), 7.5 (m, 1H),7.8 (dd, 1H).

Example 1 Crystalline4′-(5-Aminomethyl-2-ethoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicAcid t-Butyl Ester

5-Bromo-2-ethoxy-3H-imidazole-4-carbaldehyde (22.0 g, 100 mmol, 1.1eq.), 4′-bromomethyl-3′-fluorobiphenyl-2-carboxylic acid t-butyl ester(33.0 g, 90 mmol, 1 eq.), and Bu₄NBr (1.6 g, 5 mmol, 0.05 eq.) weredissolved in toluene (400 mL) and 1N NaOH (120 mL, 120 mmol, 1.2 eq.).The resulting mixture was stirred at 27° C. for 48-60 hours. The toluenelayer was separated, washed with water (2×200 mL), then removed bydistillation. EtOH (350 mL) was added to the residue and the mixture washeated to 50-60° C. until the solids dissolved. The mixture was cooledto room temperature over 4 hours, then cooled to 4° C. and stirred at 4°C. for 4 hours. The solids were filtered off, washed with cold EtOH (60mL) and dried at room temperature under vacuum for 24 hours to yieldintermediate (1a) (˜39 g).

Intermediate (1a) (20.0 g, 40 mmol, 1 eq.), potassium ethyltrifluoroborate (7.1 g, 52 mmol, 1.3 eq.), palladium(II) acetate (224mg, 1 mmol, 0.025 eq.), cataCXium®A (butyldi-1-adamantylphosphine;CAS#321921-71-5; 538 mg, 1.45 mmol, 0.04 eq.), and Cs₂CO₃ (45 g, 138mmol, 3.45 eq.) were dissolved in toluene (240 mL) and water (80 mL).The mixture was flushed with nitrogen (3×) under vacuum, then heated to90° C. for 16 hours. The mixture was then cooled to room temperature andthe layers were separated. The organic layer was washed with water(2×200 mL) then distilled under reduced pressure to yield an oil. Theoil was dissolved in EtOH (240 mL). Water (80 mL) was added and themixture was stirred for 30 minutes. The mixture was filtered to removesolids, the solids were washed with 75% EtOH (130 mL), and the filtratecollected to yield intermediate (1b) in an EtOH solution, which was useddirectly in the next step.

The EtOH solution of intermediate (1b) (10 mmol, 1 eq.) was combinedwith hydroxylamine hydrochloride (27.2 g, 52 mmol, 1.3 eq.) and NaHCO₃(35.2 g, 3.45 eq.). The mixture was stirred at 40° C. for 24 hours, thencooled to room temperature. The precipitant was filtered off, washedwith 75% EtOH (100 mL) and 50% EtOH (200 mL), then dried under reducedpressure at 30° C. for 24 hours to yield intermediate (1c) (15 g).

Intermediate (1c) (5 g) was combined with EtOH (100 mL), NH₄OH (28%, 6and Raney nickel (wet 10 g) to form a slurry. The mixture was degassedunder nitrogen (3×), degassed under hydrogen (3×), then stirred underhydrogen (1 atm) for 3 hours. The mixture was filtered to remove thecatalyst and the solids were washed with EtOH (20 mL). The filtrate wasthen treated with charcoal (0.5 g) and filtered again. The filtrate wasthen distilled under vacuum to yield an oil. Heptanes were added (50 mL)and the mixture distilled to an oil (2×). The remaining oil wasdissolved in heptanes (60 mL) by heating the mixture and stirring at 4°C. for 24 hours. The solids were then filtered, washed with coldheptanes (10 mL), and dried at room temperature for 24 hours to yieldthe title compound as a crystalline material (3.8 g).

Preparation 3 (S)-2-Acetylsulfanyl-4-methylpentanoic Acid

D-Leucine (8.2 g, 62.7 mmol) was dissolved in 3.0M HBr in water (99 mL,0.3 mol) and cooled to 0° C. A solution of NaNO₂ (6.9 g, 100 mmol) inwater (11.3 mL, 627 mmol) was slowly added over 20 minutes. The mixturewas stirred at 0° C. for 3 hours and then extracted twice with ethylether, washed with water then saturated aqueous NaCl, dried over MgSO₄,filtered, and concentrated to afford (R)-2-bromo-4-methylpentanoic acid(11.5 g) as an off-yellow oil. This was taken on to the next stepwithout further purification.

Thioacetic acid (4.2 g, 54.4 mmol) and DMF (100 mL, 1.0 mol) werecombined, and the mixture cooled in an ice bath. Sodium carbonate (5.8g, 54.4 mmol) was added. After 30 minutes, (R)-2-bromo-4-methylpentanoicacid (10.1 g, 51.8 mmol) in DMF (20 mL) was added dropwise and themixture was stirred at 0° C. to room temperature over 6 hours. Themixture was diluted with 100 mL EtOAc and extracted with 100 mL of a 1:11N HCl: saturated aqueous NaCl solution. The layers were separated andthe aqueous phase was extracted with additional EtOAc (100 mL). Theorganics were combined, washed with saturated aqueous NaCl, dried overMgSO₄, filtered, and concentrated under reduced pressure. The recoveredoil was dissolved into diisopropyl ether (45 mL, 320 mmol) and chilledat 0° C. Dicyclohexylamine (10.1 mL, 50.7 mmol) was added dropwise andthe solid was allowed to crash out of solution. After stirring for anadditional 30 minutes the material was filtered and washed with 75 mLcold diisopropyl ether. The recovered solid (14 g) was suspended in 100mL EtOAc. 150 mL of 5% KHSO₄ was added and the layers were separated.The organic was washed with saturated aqueous NaCl, dried over MgSO₄,filtered, and concentrated under reduced pressure. The recovered oil wasthen azeotroped (3×25 mL toluene) to yield the title compound (6.1 g) asa dicyclohexylamine salt.

Example 2 Crystalline4′-{5-[((S)-2-Acetylsulfanyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicAcid

Crystalline4′-(5-aminomethyl-2-ethoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (dicyclohexylamine salt; 18 g, 40 mmol, 1 eq.),(S)-2-acetylsulfanyl-4-methylpentanoic acid (18 g, 48 mmol, 1.2 eq.),and HCTU (19 g, 48 mmol, 1.2 eq.) were combined in a pre-chilled vessel(0° C. for 10 minutes) and cold DCM (240 mL) was added. The mixture wasstirred at 1±2° C. for 5-15 hours. 4% NaHCO₃ (200 mL) was added and themixture was stirred for 15 minutes. The DCM layer was separated anddistilled to ˜100 mL. IPAc (150 mL) was added and distill to 150 mL.Additional IPAc (200 mL) was added and the mixture was washed with 4%NaHCO₃ (2×200 mL) and water (200 mL). The solution was stirred with 15%NH₄Cl (300 mL) for 15 minutes, the pH was adjusted to 5.5 with 1N HCl,and then stirred for 1 hour. The solids were filtered off. The filtratewas washed with IPAc (50 mL), and the IPAc layer separated. The IPAclayer was stirred with 15% NH₄Cl (200 mL) for 3 hours and any solidsfiltered off. The filtrate was washed with saturated aqueous NaCl (150mL) and distilled under vacuum to ˜60 mL. DCM (50 mL) was added anddistilled off DCM (200 mL) was added and the mixture was cooled 0-5° C.TFA (70 mL) was added slowly (slightly exothermic) at below 15° C., andthe mixture was stirred at 20° C. for 16 hours. The mixture wasconcentrated to ˜150 ml, and IPAc (150 mL) was added. The mixture wasdistilled to ˜150 mL. Additional IPAc (150 mL) was added, and againdistilled to ˜150 mL. IPAc (200 mL) was added and the resulting solutionwas slowly added to pre-cooled K₂CO₃ (52 g) in water (250 mL) at below10° C. (mildly exothermic, pH>7 must >6 during quench) over 15 minutes.The pH was monitored during the transfer, and additional base (8 g) wasadded when the pH dropped below 6. The IPAc layer was separated andwashed with saturated aqueous NaCl (150 mL). The IPAc solution wasdistilled to ˜50 mL. MTBE (100 mL) was added and the mixture distilledto ˜50 mL. Additional MTBE (100 mL) was added and the mixture wasstirred at room temperature for 3 hours, forming a slurry, which wasthen stirred at 4° C. for 16 hours. The solids were filtered off andwashed with MTBE/diisopropyl ether (1:1; 100 mL). The solids were thendried at room temperature for 60 hours under nitrogen to yield the titlecompound as a crystalline material (18.2 g).

Example 3 Crystalline4′-{2-Ethoxy-4-ethyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicAcid

Crystalline4′-{5-[((S)-2-acetylsulfanyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid (2.3 g, 4 mmol, 1 eq.) and DTT (62 mg, 0.4 mmol, 0.1 eq.) wasdissolved in MeOH (30 mL). The resulting solution was degassed withnitrogen (3 times) and cooled at 0° C. NaOMe (25% in MeOH, 1.7 mL) wasadded and the mixture was stirred at 0° C. for 30 minutes. AcOH (3 g, 50mmol, 4 eq.) was added to quench the reaction at 0° C. The mixture waswarmed to 20° C. Deionized water (10 mL) was added slowly. The mixturewas stirred at 20° C. for 3 hours and then stirred at 4° C. for 1 houruntil precipitates were formed. The solids were filtered and washed withMeOH/H₂O (2:1; 30 mL), then dried under nitrogen at 20° C. for 48 hoursto yield the title crystalline compound (1.2 g).

Example 4 Powder X-Ray Diffraction

Powder X-ray diffraction patterns were obtained with a Rigaku MiniflexPXRD diffractometer using Cu Kα (30.0 kV, 15.0 mA) radiation. Theanalysis was performed with the goniometer running in continuous-scanmode of 2° (2θ) per min with a step size of 0.03° over a range of 2 to40° in two-theta angle. Samples were prepared on quartz specimen holdersas a thin layer of powdered material. The instrument was calibrated witha silicon metal standard, within ±0.02° two-theta angle.

A representative PXRD pattern for a sample of the crystalline compoundof Example 1 is shown in FIG. 1. A representative PXRD pattern for asample of the crystalline compound of Example 2 is shown in FIG. 3. Thenumerous intense powder diffraction peaks and relatively flat baselinedepicted in FIGS. 1 and 3 strongly indicated that the crystallinecompounds of formula IIa and Ma possessed good crystallinity.

Example 5 Thermal Analysis

Differential scanning calorimetry (DSC) was performed using a TAInstruments Model Q-100 module with a Thermal Analyst controller. Datawere collected and analyzed using TA Instruments Thermal Solutionssoftware. A 2.05 mg sample of the crystalline compound of Example 1 wasaccurately weighed into a covered aluminum pan. After a 5 minuteisothermal equilibration period at 22° C., the sample was heated using alinear heating ramp of 10° C./min from 22° C. to 250° C. Arepresentative DSC thermograph is shown in FIG. 2.

The DSC thermograph demonstrates that this crystalline compound hasexcellent thermal stability with a melting point at about 76.0° C. andno thermal decomposition below 150.0° C. The non-complex thermal profiledoes not show any undesired endothermic or exothermic peak prior to themelting endotherm at 76.0° C., which suggests that this crystallinesolid is most likely an anhydrous crystalline form.

A representative TGA trace is shown in FIG. 2, and indicates that asample of the crystalline compound of Example 1 lost a small amount(<0.5%) of weight from room temperature to 150.0° C., which isconsistent with the loss of residual moisture or solvent.

A 1.12 mg sample of the crystalline compound of Example 2 was similarlyevaluated. A representative DSC thermograph is shown in FIG. 4. The DSCthermograph demonstrates that this crystalline compound has excellentthermal stability with a melting point at about 130.9° C. and no thermaldecomposition below 150.0° C. The non-complex thermal profile does notshow any undesired endothermic or exothermic peak prior to the meltingendotherm at 130.9° C., which suggests that this crystalline solid ismost likely an anhydrous crystalline form.

A representative TGA trace is shown in FIG. 4, and indicates that asample of the crystalline compound of Example 1 lost a small amount(<0.5%) of weight from room temperature to 150.0° C., which isconsistent with the loss of residual moisture or solvent.

While the present invention has been described with reference tospecific aspects or embodiments thereof, it will be understood by thoseof ordinary skilled in the art that various changes can be made orequivalents can be substituted without departing from the true spiritand scope of the invention. Additionally, to the extent permitted byapplicable patent statutes and regulations, all publications, patentsand patent applications cited herein are hereby incorporated byreference in their entirety to the same extent as if each document hadbeen individually incorporated by reference herein.

What is claimed is:
 1. A process for preparing a compound of formula II:

or a salt thereof; where R¹ is —C₁₋₆ alkyl; R² is —O—C₁₋₅alkyl; and P is a carboxylic acid protecting group; the process comprising the steps of: (a) reacting a compound of formula I:

with a potassium-C₁₋₆alkyl-trifluoroborate reagent in the presence of a palladium-phosphine catalyst to form a compound of formula 3:

(b) reacting the compound of formula 3 with hydroxylamine or a salt thereof to form a compound of formula 4:

and (c) reacting the compound of formula 4 with a reducing agent to form a compound of formula II or a salt thereof.
 2. The process of claim 1, where the palladium-phosphine catalyst is a combination of a palladium catalyst and a source of phosphine.
 3. The process of claim 2, where the palladium catalyst is palladium(II)acetate and the source of phosphine is di(1-adamantyl)-n-butylphosphine.
 4. The process of claim 1, where the reducing agent is hydrogen/Raney nickel or Pd/C.
 5. The process of claim 1, further comprising the step of preparing a crystalline form of the compound of formula II. 